Glycosylation: mechanisms, biological functions and clinical implications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 5, 2024

Protein post-translational modification (PTM) is a covalent process that occurs in proteins during or after translation through the addition removal of one more functional groups, and has profound effect on protein function. Glycosylation most common PTMs, which polysaccharides are transferred to specific amino acid residues by glycosyltransferases. A growing body evidence suggests glycosylation essential for unfolding various activities organisms, such as playing key role regulation function, cell adhesion immune escape. Aberrant also closely associated with development diseases. Abnormal patterns linked emergence health conditions, including cancer, inflammation, autoimmune disorders, several other However, underlying composition structure glycosylated have not been determined. It imperative fully understand internal differential expression glycosylation, incorporate advanced detection technologies keep knowledge advancing. Investigations clinical applications focused sensitive promising biomarkers, effective small molecule targeted drugs emerging vaccines. These studies provide new area novel therapeutic strategies based glycosylation.

Language: Английский

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Protein misfolding and amyloid nucleation through liquid–liquid phase separation

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(10), P. 4976 - 5013

Published: Jan. 1, 2024

Protein misfolding and amyloid aggregation, linked to neurodegenerative diseases, can result from liquid–liquid phase separation (LLPS) a subsequent liquid-to-solid transition. This represents LLPS as generic mechanism in nucleation.

Language: Английский

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Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(5), P. 2805 - 2838

Published: Feb. 19, 2024

Post-translational modifications (PTMs) endow proteins with new properties to respond environmental changes or growth needs. With the development of advanced proteomics techniques, hundreds distinct types PTMs have been observed in a wide range from bacteria, archaea, and eukarya. To identify roles these PTMs, scientists applied various approaches. However, high dynamics, low stoichiometry, crosstalk between make it almost impossible obtain homogeneously modified for characterization site-specific effect individual PTM on target proteins. solve this problem, genetic code expansion (GCE) strategy has introduced into field studies. Instead modifying after translation, GCE incorporates amino acids during thus generating site-specifically at positions. In review, we summarize systems orthogonal translation installation PTMs.

Language: Английский

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Interplay between posttranslational modifications and liquid‒liquid phase separation in tumors

Cancer Letters, Journal Year: 2024, Volume and Issue: 584, P. 216614 - 216614

Published: Jan. 19, 2024

Language: Английский

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The role of O-GlcNAcylation in RNA polymerase II transcription

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(3), P. 105705 - 105705

Published: Feb. 2, 2024

Eukaryotic RNA polymerase II (RNAPII) is responsible for the transcription of protein-coding genes in cell. Enormous progress has been made discovering protein activities that are required to occur, but effects post-translational modifications (PTMs) on RNAPII transcriptional regulation much less understood. Most our understanding relates cyclin-dependent kinases (CDKs), which appear act relatively early transcription. However, it becoming apparent other PTMs play a crucial role cycle, and doubtful any sort complete this attainable without spectra occur machinery. Among these O-GlcNAcylation. Recent experiments have shown O-GlcNAc PTM likely prominent This review will cover O-GlcNAcylation during initiation, pausing, elongation, hopefully be interest both researchers. In current model RNAPII-dependent transcription, recruited promoter by members preinitiation complex (PIC: generally defined as TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH, RNAPII, Mediator (1Schier A.C. Taatjes D.J. Structure mechanism machinery.Genes Development. 2020; 34: 465-488Crossref PubMed Scopus (0) Google Scholar), presumably DNA-binding activator well). TFIIH helicase activity ribonucleotides begin initiation melting DNA start site region (TSS) Scholar, 2Thomas M.C. Chiang C.-M. The general machinery cofactors.Crit. Rev. Biochem. Mol. Biol. 2006; 41: 105-178Crossref (643) Scholar) giving access single-stranded synthesis. It now thought most genes, instead residing PIC, occurs enters transcriptionally engaged, paused state approximately 50 nucleotides downstream TSS through interactions with DRB Sensitivity-Inducing Factor (DSIF) Negative Elongation (NELF), misalign active prevent elongation (3Adelman K. Lis J.T. Promoter-proximal pausing II: emerging roles metazoans.Nat. Genet. 2012; 13: 720-731Crossref (842) 4Core L. Adelman nexus gene regulation.Genes Dev. 2019; 33: 960-982Crossref (272) 5Guo J. Price D.H. control.Chem. 2013; 113: 8583-8603Crossref (93) 6Vos S.M. Farnung Urlaub H. Cramer P. Pol II–DSIF–NELF.Nature. 2018; 560: 601-606Crossref (207) Scholar). Paused populations chromatin immunoprecipitation-sequencing (ChIP-seq) assays directed against various nascent RNA-seq approaches (7Wissink E.M. Vihervaara A. Tippens N.D. Nascent analyses: tracking its regulation.Nat. 20: 705-723Crossref (124) These show 20 70% Release into productive via phosphorylation DSIF NELF (by CDK9), releasing while remains bound positive factor (8Dollinger R. Gilmour D.S. Regulation proximal metazoans.J. 2021; 433166897Crossref (36) (Fig. 1). PARP-1 also stimulates pause release ADP-ribosylation (9Gibson B.A. Zhang Y. Jiang Hussey K.M. Shrimp J.H. Lin et al.Chemical genetic discovery PARP targets reveals elongation.Science. 2016; 353: 45-50Crossref (259) MYC (10Rahl P.B. C.Y. Seila Flynn R.A. McCuine S. Burge C.B. al.c-Myc regulates release.Cell. 2010; 141: 432-445Abstract Full Text PDF (977) TRIM28 (11Yang Lu Chen C. Lyu Cole R.N. Semenza G.L. HIF-1 Interacts DNA-PK activate target response hypoxia.Nat. Commun. 2022; 316Crossref (28) 12Bunch Zheng X. Burkholder Dillon S.T. Motola Birrane G. al.TRIM28 promoter-proximal release.Nat. Struct. 2014; 21: 876-883Crossref (104) 13McNamara R.P. Reeder J.E. McMillan E.A. Bacon C.W. McCann J.L. D'Orso I. KAP1 recruitment 7SK snRNP promoters enables II.Mol. Cell. 2015; 61: 39-53Abstract PAF (14Chen F.X. Woodfin A.R. Gardini Rickels Marshall S.A. Smith E.R. al.PAF1, molecular regulator II.Cell. 162: 1003-1015Abstract (159) 15Yu M. Yang W. Ni T. Tang Z. Nakadai Zhu al.RNA II-associated 1 II.Science. 350: 1383-1386Crossref (161) FACT (16Tettey T.T. Gao Shao Li Story Chitsazan A.D. al.A pausing.Cell Rep. 27: 3770-3779.e7Abstract (34) 17Wada Orphanides Hasegawa Kim D.K. Shima D. Yamaguchi al.FACT relieves DSIF/NELF-mediated inhibition functional differences between P-TEFb TFIIH.Mol. 2000; 5: 1067-1072Abstract CDK7 (18Glover-Cutter Larochelle S.S. Erickson B. Shokat Fisher al.TFIIH-Associated Cdk7 kinase functions C-terminal domain Ser7 residues, termination Cell 2009; 29: 5455-5464Crossref (248) SIRT6 (19Etchegaray J.P. Zhong Henriques Ablondi E. al.The histone deacetylase restrains pausing.Mol. 75: 683-699Abstract (45) U2 (20Caizzi Monteiro-Martins Schwalb Lysakovskaia Schmitzova Sawicka al.Efficient requires function.Mol. 81: 1920-1934Abstract ARID1A (21Trizzino Barbieri Petracovici Wu Welsh Owens T.A. tumor suppressor controls global II.Cell 23: 3933-3945Abstract (67) Integrator (22Wagner E.J. Tong complex.Mol. 2023; 83: 416-427Abstract 23Huang K.L. Jee Stein Elrod Mascibroda L.G. al.Integrator recruits phosphatase 2A facilitate termination.Mol. 80: 345-358Abstract (85) 24Beckedorff F. Blumenthal Dasilva L.F. Aoi Cingaram P.R. Yue human integrator facilitates endonucleolytic cleavage transcripts.Cell 32107917Abstract (51) 25Elrod Huang Tatomer D.C. Wilusz Wagner attenuates at genes.Mol. 76: 738-752Abstract (114) 26Gardini Baillat Cesaroni Hu Marinis J.M. following activation.Mol. 56: 128-139Abstract (118) 27Stadelmayer Micas Gamot Martin Malirat N. Koval NELF-mediated pause/release processivity coding genes.Nat. 5531Crossref all and/or release. function not clear. Some suggested rate-limiting step others suggest necessary rapid induction former lacks evidence being an actual biochemically step. Others concluded experimentally supported either (28Gilchrist D.A. Fromm dos Santos Pham L.N. McDaniel I.E. al.Regulating regulators: pervasive stimulus-responsive networks.Genes 26: 933-944Crossref regulated step, requiring stimulate elongation. entire process dynamic one continuous those polymerases (29Erickson Sheridan R.M. Cortazar Bentley D.L. Dynamic turnover complexes promoters.Genes 32: 1215-1225Crossref (49) 30Krebs Imanci Hoerner Gaidatzis Burger Schübeler Genome-wide single-molecule footprinting high promoters.Mol. 2017; 67: 411-422.e4Abstract (117) 31Steurer Janssens R.C. Geverts Geijer M.E. Wienholz Theil A.F. al.Live-cell analysis endogenous GFP-RPB1 uncovers initiating promoter-paused Polymerase II.Proc. Natl. Acad. Sci. U. 115: E4368-E4376Crossref (121) 32Darzacq Shav-Tal de Turris V. Brody Shenoy Phair R.D. al.In vivo dynamics transcription.Nat. 2007; 14: 796-806Crossref (515) may steps, just Since prevalent so many might represents default ground promoter. Why? Firstly, exist state. Secondly, because NTPs freely diffusing, expect soon PIC forms, initiated paused, engaged itself, population responds tissue-specific induced activators, such NF-κB, HIF-1α, HSF. Additionally, Levens colleagues level stochastic noise (variance) using multiple, distinct kinetic steps (33Weber Liu Collins operates expanded fine-tune c-myc expression.Mol. 2005; 25: 147-161Crossref (57) terms involved research largely focused how they regulate kinases: CDK7, CDK8, CDK9, CDK12/13, phosphorylate serine threonine residues (34Fisher CDK RNAP over 'til it's over?.Transcription. 8: 81-90Crossref part phosphorylates (CTD) RPB1 subunit. proper (35Larochelle Amat Glover-Cutter Sanso Allen J.J. al.Cyclin-dependent control initiation-to-elongation switch II.Nat. 19: 1108-1115Crossref (281) CDK9 CTD, along mentioned above. more than substrates, CDKs do well (36Sansó Levin R.S. Lipp Wang V.Y.-f.F. Greifenberg A.K. Quezada al.P-TEFb Xrn2 revealed chemical screen Cdk9 substrates.Genes 30: 117-131Crossref CDK8 module activator-dependent coactivator (37Poss Z.C. Ebmeier C.C. regulation.Crit. 48: 575-608Crossref (268) 38Allen B.L. complex: central 16: 155-166Crossref (607) CDK12/13 seems some CTD substrate (39Greenleaf A.L. Human CDK12 CDK13, multi-tasking new millenium.Transcription. 10: 91-110Crossref (64) 40Liang Gilmore Florens Washburn M.P. al.Characterization CDK13 phosphorylation, processing.Mol. 35: 928-938Crossref consists 52 repeats loose consensus heptad Y1S2P3T4S5P6S7. specific humans: fruit fly (D. melanogaster) 41, budding yeast (S. cerevisiae) 26 (41Eick Geyer carboxy-terminal code.Chem. 8456-8490Crossref (318) 42Jasnovidova O. Stefl code A structural view.Wiley Inter. RNA. 4: 1-16Crossref 43Jeronimo C.l.C. Bataille Robert F.o.F. writers, readers, 8491-8522Crossref (89) 44Harlen Churchman L.S. beyond: domain.Nat. 18: 263-273Crossref (291) remarkably intrinsically disordered domain. first contain 21 Y1S2P3T4S5P6S7 cerevisiae 19) 5 less-mentioned asparagine (N) position 7. Heptads 27 further deviate: eight lysine (K), six (T), each arginine (R), glutamic acid (E), valine (V), glycine (G) (45Hsin Manley coordinates processing.Genes 2119-2137Crossref (465) 7-heptad repeat reminiscent α-helix K, R, T potentially substrates methyltransferase (K, R), or (see below) (S, T). then greatly affect conformational space occupied CTD. under debate. deletions humans lethal (46Bartolomei M.S. Halden N.F. Cullen C.R. Corden Genetic repetitive carboxyl-terminal largest subunit mouse 1988; 330-339Crossref 47Nonet Sweetser Young Functional redundancy polymorphism large 1987; 50: 909-915Abstract (233) severe formation (48Chapman Conrad Eick Role mammalian nonconsensus stability cell proliferation.Mol. 7665-7674Crossref (48) 49Meininghaus Chapman Horndasch Conditional expression cells. Deletion affects transcription.J. Chem. 275: 24375-24382Abstract (70) More recent indicate post-initiation events (50Gerber Roeder R.G. essential activity.J. 432: 5489-5498Crossref although there disagreement here (51Lux Albiez Heidinger Meininghaus Brack-Werner al.Transition from II.Nucleic Acids Res. 5139-5144Crossref (13) cell-free systems, (52Zehring W.A. Greenleaf Sp1 vitro.J. 1990; 265: 8351-8353Abstract 53Zehring Lee Weeks J.R. Jokerst accurate vitro.Proc. 85: 3698-3702Crossref 54Serizawa Conaway J.W. Phosphorylation basal transcription.Nature. 1993; 363: 371-374Crossref (151) immediately after predominantly five data suggests two too 55Vihervaara Versluis Himanen S.V. PRO-IP-seq tracks nucleotide resolution.Nat. 7039Crossref Serine located 5′ increases towards 3′ end (56Jeronimo Collin CTD: increasing complexity low-complexity domain.J. 428: 2607-2622Crossref (92) marks often used evaluate clear whether Threonine four perhaps interesting phosphorylated seeming gene- signal-dependent efficacy (57Kempen Dabas Ansari A.Z. Phantom Mark: enigmatic phospho-Threonine 4 modification II.WIREs 14e771Crossref Post-transcriptionally, capping enzymes splicing factors (58Saldi M.A. Coupling pre-mRNA splicing.J. 2623-2635Crossref 59Tellier Zaborowska Neve Nojima Hester Fournier al.CDK9 PP2A coupled maturation.EMBO e54520Crossref (8) playing (60David C.J. Boyne Millhouse S.R. promotes activation U2AF65-Prp19 complex.Genes 2011; 972-983Crossref (136) 61Ryan Murthy K.G.K. Kaneko Requirements reconstituting cleavage.Mol. 2002; 22: 1684-1692Crossref 62Hirose Tacke Phosphorylated splicing.Genes 1999; 1234-1239Crossref Thus, scaffold recruiting coupling splicing. common PTM, overlooked. essentially modified glucose molecule acetylated amine added C2 carbon glucose. Like CDKs, transferase (OGT) modifies hydrolysis sugar UDP-GlcNAc. OH groups form O-glycosidic linkage N-acetylglucosamine. Mass spectrometry identified 4000 O-GlcNAcylated proteins, (63Hahne Sobotzki Nyberg Helm Borodkin V.S. van Aalten D.M.F. al.Proteome wide purification identification O-GlcNAc-modified proteins click chemistry mass spectrometry.J. Proteome 12: 927-936Crossref (132) 64Liu Q. Dou Cao al.Proteomic profiling genome-wide mapping chromatin-associated reveal O-GlcNAc-regulated genotoxic stress response.Nat. 11: 5898Crossref 65Ma Hou O-GlcNAcAtlas: database sites proteins.Glycobiology. 31: 719-723Crossref 66Ma Hart G.W. profiling: proteomes.Clin. Proteomics. 8Crossref (206) There overlaps OGT, (also release/elongation Scholar)) interactomes OGT OGA, suggesting considerable crosstalk Table 1).Table 1Shown left column components O-GlcNAcylatedO-GlcNAcylatedPausing & factorsCDK9 substratesPARP substratesOGT interactomeOGAInteractomeNELFA/CD/EYes: NELF-EYes: NELF-BTAT-SF1YesYesSPT5YesYesPARP-1YesYesSPT6YesFACTYesYesYesTop1YesYesTop2BYesYesTRIM28YesYesYesYesCDK9YesYesYesBRD4YesYesCDC73YesYesYesRTF1YesPAF1YesYesLeo1YesRPAP2HCF-1YesCapping RMNTYes DCP1BTermination XRN2YesYes INTS3/6Yes p65YesYes PP1The list based interactome (111Gao Qiu Teng Proteomic interactome: novel links epithelial-mesenchymal transition metastasis cervical cancer.Carcinogenesis. 39: 1222-1234Crossref (47) include RPB1, RPB2, p62/TFIIH, RBP7, MED1/4/9/30/15, TAF4/6/10/15, FCP1, cyclin H, OGA (89Resto B.H. Fernandez A.G. Abraham B.J. Zhao Lewis O-GlcNAcase SPT5 TIF1beta.J. 291: 22703-22713Abstract Open table tab globular containing 13.5 helical tetratricopeptide (TPR) TPR structure participates recognition channels (67Kenneth Allan Ratajczak Versatile domains accommodate different modes function.Cell Stress Chaperones. 353-367Crossref 68Janetzko Walker making sweet modification: transferase.J. 289: 34424-34432Abstract 69Joiner C.M. Hammel F.A. Janetzko Protein engage lumen transferase's ways.Biochemistry. 60: 847-853Crossref (14) acts protease cleave Oct-1 Host (HCF-1) mature (70Lazarus M.B. Kapuria Bhuiyan Zandberg W.F. al.HCF-1 cleaved transferase.Science. 342: 1235-1239Crossref (142) recently, noncatalytic were described (71Levine Z.G. Potter S.C. Joiner Fei G.Q. Nabet Sonnett al.Mammalian proliferation transferase.Proc. 118e2016778118Crossref aminidase (OGA) removes GlcNAc proteins. Its specificity debate, overall, understood [see (72Stephen H.M. Adams T.M. Wells Regulating mechanisms selection cycling OGA.Glycobiology. 724-733Crossref (32) 73Joiner Structural characterization enzymes: insights catalytic mechanisms.Curr. Opin. 97-106Crossref (58) in-depth discussion enzyme

Language: Английский

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Phase separation-mediated biomolecular condensates and their relationship to tumor

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 21, 2024

Abstract Phase separation is a cellular phenomenon where macromolecules aggregate or segregate, giving rise to biomolecular condensates resembling "droplets" and forming distinct, membrane-free compartments. This process pervasive in biological cells, contributing various essential functions. However, when phase goes awry, leading abnormal molecular aggregation, it can become driving factor the development of diseases, including tumor. Recent investigations have unveiled intricate connection between dysregulated tumor pathogenesis, highlighting its potential as novel therapeutic target. article provides an overview recent research, with particular emphasis on role tumor, implications, outlines avenues for further exploration this intriguing field.

Language: Английский

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Biomolecular Condensates: Structure, Functions, Methods of Research

Biochemistry (Moscow), Journal Year: 2024, Volume and Issue: 89(S1), P. S205 - S223

Published: Jan. 1, 2024

Language: Английский

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A tale of two sugars: O-GlcNAc and O-fucose orchestrate growth, development, and acclimation in plants

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Glycosylation of serine/threonine-rich intrinsically disordered regions of membrane-associated proteins in streptococci

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 29, 2025

Language: Английский

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Recent advances in chemical synthesis of O-linked glycopeptides and glycoproteins: An advanced synthetic tool for exploring the biological realm

Current Opinion in Chemical Biology, Journal Year: 2023, Volume and Issue: 77, P. 102405 - 102405

Published: Oct. 26, 2023

Language: Английский

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